title: GRP78 secreted by tumor cells stimulates differentiation of bone marrow mesenchymal stem cells to cancer-associated fibroblasts.
abstract: Cancer-associated fibroblasts (CAFs), one type of tumor-associated stromal cells, have been shown to provide a favorable environment for the malignant tumor progression. Extensive reports have demonstrated that mesenchymal stem cells (MSCs) can function as precursors for CAFs. However, the mechanisms by which tumor cells induce the transition of MSCs to CAFs have not been well established. GRP78, traditionally known as an endoplasmic reticulum (ER) chaperone, has been identified to overexpress in a variety of tumor entities and be involved in promoting survival and chemoresistance of tumor cells. Here, we interrogated the role of GRP78 in the generation of CAFs from MSCs. The results showed that GRP78 treatment induced expression of α-smooth muscle actin (α-SMA), a marker for CAFs, in human bone marrow mesenchymal stem cells (HBMSCs) as well as murine bone marrow mesenchymal stem cells (BMMSCs). This phenomenon was correlated with the stimulated phosphorylation of Smad2/3. Furthermore, the GRP78-induced α-SMA expression in HBMSCs was obviously attenuated by SB431542, a TGF-β type I receptor kinase inhibitor. Taken together, the present data suggested that tumor-derived secreted GRP78 elicited the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) to CAFs through activating TGF-β/Smad signaling pathway, which may represent a novel mechanism for transition of BMSCs to CAFs and a hitherto unknown function of GRP78 in the tumor microenvironment.
authors.affiliation: Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Peng
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Li
authors.forename: Zhuoyu
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D017077:Culture Media, Conditioned; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: BMMSCs; BMSCs; BiP; CAFs; Cancer-associated fibroblasts; ECL kit; ER; FBS; GRP78; HBMSCs; HRP-tagged secondary antibodies; IPTG; MSCs; Mesenchymal stem cells; PBS; SDF-1; SE; TCM; bone marrow-derived mesenchymal stem cells; cDNA; cancer-associated fibroblasts; complementary DNA; endoplasmic reticulum; enhanced chemiluminescence kit; fetal bovine serum; glucose-regulated protein 78; horseradish peroxidase-tagged secondary antibodies; human bone marrow mesenchymal stem cells; immunoglobulin heavy chain binding protein; isopropyl-β-d-thiogalactoside; mesenchymal stem cells; murine bone marrow mesenchymal stem cells; p values; phosphate-buffered saline; probability values; standard error; stromal cell-derived factor 1; tumor-conditioned medium; α-SMA; α-Smooth muscle actin; α-smooth muscle actin